Abstract 5633: Beta-Glucan treatment restricts liver metastasis in pancreatic cancer
Authors: Stacy K. Thomas, Shaanti Choi-Bose, Heather Coho, Christopher Casella, Meredith L. Stone, Max M. Wattenberg, Gregory L. Beatty
Journal: Cancer Research (2022)

Abstract Introduction: For most patients with pancreatic ductal adenocarcinoma (PDAC), metastatic disease is the main cause of mortality with the liver being the most common site of metastasis. In the liver, macrophages are the most abundant immune cell subset, yet their role in regulating liver metastasis remains poorly understood. Two distinct macrophage populations exist in the liver: liver-resident Clec4f+F4/80+ Kupffer cells (KCs) and Clec4fnegF4/80+ bone marrow derived macrophages (BMDMs). Here, we sought to understand the impact of these macrophage subsets on liver metastasis and the ability of a myeloid agonist, a β-glucan (BG), to skew macrophages towards an anti-metastatic phenotype. Methods: C57BL/6 mice were given an intraportal (iPo) injection of an LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre;LSL-Rosa26-Yfp (KPCY) cell line to model liver metastasis. Mice were necropsied 2 days later to measure metastatic seeding of cancer cells or 12-14 days later to assess metastatic lesion outgrowth. Liver metastatic burden and immune cell populations were analyzed by flow cytometry and immunohistochemistry. In macrophage depletion experiments, liver macrophages were depleted using clodronate encapsulated liposomes (CEL) delivered intraperitoneally. In studies involving BG treatment, weekly intravenous administration of BG began 2 days prior to iPo injection of cancer cells. Results: Liver macrophage depletion did not influence metastatic seeding in the liver; but, did inhibit the outgrowth of established metastatic colonies. Histological analysis showed that Clec4f+ KCs were excluded from metastatic lesions, whereas BMDMs actively infiltrated. BMDM infiltration into lesions was also largely unaffected by CEL treatment. To stimulate macrophages with anti-metastatic activity, BG was administered systemically and found to bind to &amp;gt;95% of KCs but only 30% of BMDMs and 20-35% of other immune cell populations. BG treatment attenuated liver metastasis when given during both the seeding and outgrowth phases of metastasis (mean metastatic burden as % live cells in liver: 1%, BG vs 6.5%, control, p&amp;lt;0.0001). Analysis of metastatic lesions in BG treated mice by histology showed smaller lesions (mean size: 0.9mm2, BG vs 1.5mm2, control, p=0.09), decreased proliferating cancer cells (mean # of proliferating cancer cells per unit metastatic area: 480, BG vs 810, control, p&amp;lt;0.0001), and increased numbers of CD3+ T cells at the periphery of lesions compared to lesions from control mice (mean # of T cells per mm2 metastatic area: 300, BG vs 135, control, p&amp;lt;0.0001). The efficacy of BG to restrict liver metastasis was dependent on liver macrophages. Conclusions: Taken together, these findings suggest that, while liver macrophages can be coopted to support metastatic outgrowth, treatment with a β-glucan, as a myeloid agonist is a novel strategy to engender liver macrophages with anti-metastatic activity. Citation Format: Stacy K. Thomas, Shaanti Choi-Bose, Heather Coho, Christopher Casella, Meredith L. Stone, Max M. Wattenberg, Gregory L. Beatty. Beta-Glucan treatment restricts liver metastasis in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5633.